The purpose of this R01 competitive renewal (response to NIDDK RFA 0025) is to request funds to complete recruitment, randomization and data analysis of a pilot study designed to determine the safety and efficacy (proteinuria) of combining an angiotensin converting enzyme inhibitor (ACEi) with either an angiotensin type 1 receptor blocker (ARB) or a mineralocorticoid antagonist (MRA) as compared to an ACE inhibitor alone in diabetics with nephropathy. This study is a randomized, double-blind placebo-controlled trial in a multiethnic cohort of type 1 and type 2 diabetics with persistent urine albumin/ creatinine ratio >= 300 mg/g despite maximally-dosed ACEi (lisinopril 80 mg per day or ramipril 40 mg per day). Study subjects are randomized into one of three groups to receive add-on treatment with placebo or spironolactone (25 mg/day) or losartan (100 mg/day) for 48 weeks with similar blood pressure control (< 130/< 80 mmHg). Ambulatory blood pressure monitoring is performed at baseline and periodically throughout the study. In the past 15 months we successfully built our study team, database and recruitment strategy. We screened more than 2500 potential participants, conducted 37 screening visits and successfully randomized 12 patients including 2 white, 6 black and 4 Hispanics among whom 40% are type 1 and 60% are type 2 diabetics between the ages of 20-60. To date, there have been no drop outs. We plan to complete recruitment and randomization of about 90 participants, of whom 78 are expected to complete the study (15% drop our rate). This will provide 90% power to detect a 30% decrease in urinary albumin/creatinine ratio in either experimental group as compared to the placebo group (o=0.05, ANOVA). Recruitment has accelerated dramatically in the past 3 months. We expect to complete recruitment by the end of the first year and follow-up by the end of the second year of funding. We anticipate this study will: 1) establish the safety and effectiveness of maximal dose combination therapy; 2) determine feasibility of extensively utilizing 24-hour ABPM in future large-scale trials designed to establish BP independent renoprotective effects of specific antihypertensives; and 3) provide preliminary data for a future large-scale study to test the efficacy and safety of combining ACEi therapy with an ARB or a MRA on renal outcomes in diabetics.